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Phosphoprotein phosphatase 2A, a new target for Alzheimer's Disease interventio

磷蛋白磷酸酶2A，阿尔茨海默病干预新靶点

基本信息

批准号：
7998103
负责人：
Steven P. Braithwaite
金额：
$ 32.47万
依托单位：
SIGNUM BIOSCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7998103
关键词：
Accounting Affect Alzheimer&apos s Disease Alzheimer&apos s disease model American Animal Disease Models Animal Model Biochemical Biological Assay Biological Factors Biological Markers Brain Brain Diseases Cell Culture Techniques Cell Line Cells Cerebrospinal Fluid Clinical Coffee Cognitive Collaborations Consumption Cyclic AMP-Dependent Protein Kinases Data Development Disease Dose Drug Formulations Epidemiology Future Glycogen Synthase Kinase 3 Goals Human In Vitro Incidence Intervention Lead Libraries Light Link MAP Kinase Gene Measures Medical Methylation Minor Mus Nerve Degeneration Neuroblastoma Neurodegenerative Disorders Neurons Oral Administration PC12 Cells Pathology Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phase Phosphoproteins Phosphoric Monoester Hydrolases Phosphorylase a Play Prevention Property Protein Dephosphorylation Protein Kinase Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Rattus Research Research Proposals Rodent Model Role Safety Screening procedure Tauopathies Therapeutic Toxicology Transgenic Organisms Treatment Efficacy Viral Wild Type Mouse abnormally phosphorylated tau base calmodulin-dependent protein kinase II demethylation drug candidate effective intervention effective therapy hyperphosphorylated tau in vivo motor impairment mouse model novel pharmacophore pre-clinical public health relevance research study small molecule tau Proteins tau phosphorylation tau-1 tau-protein kinase

项目摘要

DESCRIPTION (provided by applicant): Abnormal hyperphosphorylation of tau plays an important role in Alzheimer's disease (AD) and other tauopathies. Current therapeutic approaches with focus on tau kinases (e.g. GSK-3, MAPK, cdk5, CK-1, PKA, CaMKII) are hindered by multiple and redundant tau phosphorylation pathways. In contrast, protein phosphatase-2A (PP2A) is the major tau phosphatase accounting for ~70% of tau dephosphorylation, and recent research shows that its expression and activity are down-regulated in AD. PP2A activity is governed by reversible carboxyl-methylation, thus inhibiting demethylation might be a promising intervention strategy to restore healthy tau phosphorylation levels. Building a screening platform around this hypothesis, we identified a small molecule SIG1012, which reduces p-tau levels in N2a cells in a dose-dependent manner and is orally efficacious in reducing p-tau in wild type mice. Preliminary pharmacological data suggests that SIG1012 has highly favorable safety and toxicology profiles. The proposed Phase I research plan is critical to validating PP2A as a pharmaceutical target for effective intervention in AD by a small molecule. It outlines specific steps for the proposed proof of concept studies of efficacy in animal models of AD. The critical 3xTg-AD mouse and (AAV)-I2 CTF rat experiments will be carried out in collaboration with Dr. Khalid Iqbal, a world- renowned expert on the role of tau in neurodegenerative diseases. Successful completion of this research proposal will lead in Phase II to formal preclinical development of SIG1012 as the "first-in-class" PP2A modulating agent for treatment of AD and other tauopathies. ) PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a progressive and fatal brain disease that afflicts over 5 million Americans today and over 27 million people worldwide. Current treatments of AD are largely unsatisfactory and development of more effective therapies represents a great unmet medical need. Successful development of this novel class of phosphoprotein modulators will provide an important additional, and potentially better, therapeutic option for people suffering from AD.

描述（由申请人提供）：tau异常高磷酸化在阿尔茨海默病（AD）和其他tau病中起重要作用。目前以tau激酶（如GSK-3、MAPK、cdk5、CK-1、PKA、CaMKII）为重点的治疗方法受到多个冗余tau磷酸化途径的阻碍。相反，蛋白磷酸酶2a （protein phosphatase- 2a, PP2A）是主要的tau磷酸酶，约占tau去磷酸化的70%，最近的研究表明其在AD中的表达和活性下调。PP2A活性受可逆羧基甲基化控制，因此抑制去甲基化可能是恢复健康的tau磷酸化水平的一种有希望的干预策略。围绕这一假设建立筛选平台，我们发现了一个小分子SIG1012，它以剂量依赖的方式降低N2a细胞中的p-tau水平，并且在野生型小鼠中口服有效降低p-tau。初步药理数据表明，SIG1012具有良好的安全性和毒理学特征。拟议的I期研究计划对于验证PP2A作为小分子有效干预AD的药物靶点至关重要。它概述了拟议的AD动物模型有效性概念验证研究的具体步骤。关键的3xTg-AD小鼠和(AAV)- i2 CTF大鼠实验将与世界知名的tau在神经退行性疾病中的作用专家Khalid Iqbal博士合作进行。该研究计划的成功完成将导致SIG1012在II期正式临床前开发，作为治疗AD和其他tau病的“一流”PP2A调节剂。